PTP1B Signaling
PTP1B is an intracellular protein tyrosine phosphatase. PTP activity is regulated by modifications of several amino acid residues in the polypeptide, such as phosphorylation of Ser residues (Brautigan and Pinault, 1993; Dadke et al., 2001; Flint et al., 1993) and oxidation of the active Cys residue in its catalytic motif (Lee et al., 1998; Meng et al., 2002), which is evolutionarily conserved among protein tyrosine phosphatases and dual specificity phosphatase family members (Andersen et al., 2001). In its reduced, active state, which is the basal state of the enzyme, PTP1B regulates a number of signaling pathways. For example, PTP1B activity antagonizes insulin signaling. Upon reception of an insulin signal by a target cell, PTP1B is reversibly oxidized, which removes the inhibitory regulation of insulin signaling by PTP1B until the enzyme returns to its reduced, active state. Other signaling pathways, for example EGF and leptin signaling, are also modulated by PTP1B activity. PTP1B is indicated in a number of human diseases, such as obesity and diabetes.
Many small molecule PTP1B inhibitors have been identified. The catalytic pocket of PTP1B tends to be highly charged and, as a result, small molecule inhibitors of PTP1B tend to be highly polar molecules. Such compounds are not passively absorbed by the human body and, thus, cannot be used as drugs via standard enteral or parenteral delivery routes. Because of these characteristics, PTP1B is seen to be an “undruggable” target (See, e.g., Cheng et al., Nat Biotech 2007).
The inability to find drugs that target this well-validated target is illustrated by the lack of clinical trials successfully completed by any of the companies pursuing PTP inhibitors. The identification and development of PTP inhibitors is highly desirable in order to address the major unmet medical need to treat PTP1B-related disorders, such as obesity and diabetes.